Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior.

The bed nucleus of the stria terminalis (BNST) is a brain region important for regulating anxiety-related behavior in both humans and rodents. Here we used a chemogenetic strategy to investigate how engagement of G protein-coupled receptor (GPCR) signaling cascades in genetically defined GABAergic BNST neurons modulates anxiety-related behavior and downstream circuit function. We saw that stimulation of vesicular γ-aminobutyric acid (GABA) transporter (VGAT)-expressing BNST neurons using hM3Dq, but neither hM4Di nor rM3Ds designer receptors exclusively activated by a designer drug (DREADD), promotes anxiety-like behavior. Further, we identified that activation of hM3Dq receptors in BNST VGAT neurons can induce a long-term depression-like state of glutamatergic synaptic transmission, indicating DREADD-induced changes in synaptic plasticity. Further, we used DREADD-assisted metabolic mapping to profile brain-wide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures, including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight that Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous GPCRs within genetically defined cell populations. We next used a microfluidics approach to profile the receptorome of single BNST VGAT neurons. This approach yielded multiple Gq-coupled receptors that are associated with anxiety-like behavior and several potential novel candidates for regulation of anxiety-like behavior. From this, we identified that stimulation of the Gq-coupled receptor 5-HT2CR in the BNST is sufficient to elevate anxiety-like behavior in an acoustic startle task. Together, these results provide a novel profile of receptors within genetically defined BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states and provide a blueprint for examining how G-protein-mediated signaling in a genetically defined cell type can be used to assess behavior and brain-wide circuit function.

Predicting the likelihood of live birth for elective oocyte cryopreservation: a counseling tool for physicians and patients.

Study question: Can a counseling tool be developed for women desiring elective oocyte cryopreservation to predict the likelihood of live birth based on age and number of oocytes frozen? Summary answer: Using data from ICSI cycles of a population of women with uncompromised ovarian reserve, an evidence-based counseling tool was created to guide women and their physicians regarding the number of oocytes needed to freeze for future family-building goals. What is known already: Elective oocyte cryopreservation is increasing in popularity as more women delay family building. By undertaking elective oocyte freezing at a younger age, women hope to optimize their likelihood of successful live birth(s) using their thawed oocytes at a future date. Questions often arise in clinical practice regarding the number of cryopreserved oocytes sufficient to achieve live birth(s) and whether or not additional stimulation cycles are likely to result in a meaningful increase in the likelihood of live birth. As relatively few women who have electively cryopreserved oocytes have returned to use them, available data for counseling patients wishing to undergo fertility preservation are limited. Study design, size, duration: A model was developed to determine the proportion of mature oocytes that fertilize and then form blastocysts as a function of age, using women with presumably normal ovarian reserve based on standard testing who underwent ICSI cycles in our program from January, 2011 through March, 2015 (n = 520). These included couples diagnosed exclusively with male-factor and/or tubal-factor infertility, as well as cycles utilizing egg donation. Age-specific probabilities of euploidy were estimated from 14 500 PGS embryo results from an external testing laboratory. Assuming survival of thawed oocytes at 95% for women <36 y and for egg donors, and 85% for women ≥36 y, and 60% live birth rate per transferred euploid blastocyst, probabilities of having at least one, two or three live birth(s) were calculated. Participants/materials, setting, method: First fresh male-factor and/or tubal-factor only autologous ICSI cycles (n = 466) were analyzed using Poisson regression to calculate the probability that a mature oocyte will become a blastocyst based on age. Egg donation cycles (n = 54) were analyzed and incorporated into the model separately. The proportion of blastocysts expected to be euploid was determined using PGS results of embryos analyzed via array comparative genomic hybridization. A counseling tool was developed to predict the likelihood of live birth, based on individual patient age and number of mature oocytes. Main results and the role of chance: This study provides an evidence-based model to predict the probability of a woman having at least one, two or three live birth(s) based on her age at egg retrieval and the number of mature oocytes frozen. The model is derived from a surrogate population of ICSI patients with uncompromised ovarian reserve. A user-friendly counseling tool was designed using the model to help guide physicians and patients. LIMITATIONS, REASONS FOR CAUTION: The data used to develop the prediction model are, of necessity, retrospective and not based on patients who have returned to use their cryopreserved oocytes. The assumptions used to create the model, albeit reasonable and data-driven, vary by study and will likely vary by center. Centers are therefore encouraged to consider their own blastocyst formation and thaw survival rates when counseling patients. Limitations, reasons for caution: Our model will provide a counseling resource that may help inform women desiring elective fertility preservation regarding their likelihood of live birth(s), how many cycles to undergo, and when additional cycles would bring diminishing returns. Study funding/competing interests: None. Trial registration number: Not applicable.

Cessation of driving and unsafe motor vehicle operation by dementia patients.

We surveyed 522 consecutive patients from a dementia clinic to assess duration of driving after disease onset and instances of unsafe motor vehicle operation in the preceding 6 months. Among the 333 patients licensed to drive at the onset of dementia, the median duration of driving after onset was 28.6 months. Patients with a clinical diagnosis of Alzheimer's disease drove significantly longer than those with other dementia syndromes. Of the 93 patients still driving at the time of the survey, approximately one third were reported to have had at least one form of unsafe motor vehicle operation in the past 6 months, including 21 patients with motor vehicle accidents. Motor vehicle accidents were associated with use of prescription medications with sedative properties and with lower subjective ratings of the patient's driving ability by the informant.

Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women.

CONTEXT: Serum estradiol (E2) levels are preserved in older reproductive-aged women with regular menstrual cycles despite declining ovarian function. OBJECTIVE: The objective of the study was to determine whether increased granulosa cell aromatase expression and activity account for preservation of E2 levels in older, regularly cycling women. DESIGN: The protocol included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. SUBJECTS: Healthy, regularly cycling older (36-45 y; n = 13) and younger (22-34 y; n = 14) women participated in the study. MAIN OUTCOME MEASURES: Hormone levels were measured in peripheral blood and follicular fluid aspirates and granulosa cell CYP19A1 (aromatase) and FSH-R mRNA expression were determined. RESULTS: Older women had higher FSH levels than younger women during the early follicular phase with similar E2 but lower inhibin B and antimullerian hormone levels. Late follicular phase serum E2 did not differ between the two groups. Follicular fluid E2 [older (O) = 960.0 [interquartile range (IQR) 765.0-1419.0]; younger (Y) = 994.5 [647.3-1426.5] ng/mL, P = 1.0], estrone (O = 39.6 [29.5-54.1]; Y = 28.8 [22.5-42.1] ng/mL, P = 0.3), and the E2 to testosterone (T) ratio (O = 109.0 ± 41.9; Y = 83.0 ± 18.6, P = .50) were preserved in older women. Granulosa cell CYP19A1 expression was increased 3-fold in older compared with younger women (P < .001), with no difference in FSH-R expression. CONCLUSIONS: Ovarian aromatase expression increases with age in regularly cycling women. Thus, up-regulation of aromatase activity appears to compensate for the known age-related decrease in granulosa cell number in the dominant follicle to maintain ovarian estrogen production in older premenopausal women.

A 'stress' test for memory dysfunction. Electrophysiologic manifestations of early Alzheimer's disease.

Long-latency event-related potentials (P300) were assessed in patients with early probable Alzheimer's disease (AD), age-matched controls, and young adults during a task that imposed various degrees of demand on memory. Although patients with AD did not differ from age-matched controls when one item had to be remembered, their P300 potential was dramatically reduced in amplitude or absent with increasing memory load. Aged controls did not differ from young adults on this measure. P300 latency, however, did not differentiate patients with AD. Thus, electrophysiological abnormalities detected in the context of mnemonic demand may provide a sensitive marker of the early stages of probable AD.

Intraventricular bethanechol infusion for Alzheimer's disease: results of double-blind and escalating-dose trials.

Ten patients with biopsy-proven Alzheimer's disease (AD) received low-dose (0.35 mg/d) intraventricular bethanechol, a muscarinic agonist, and saline placebo in a 24-week double-blind crossover design. Eight of these ten patients later participated in an open escalating-dose (to 1.75 mg/d) trial of bethanechol. Patients' drug responses were assessed by neuropsychological examination and informant measures of activities of daily living, mood disturbance, and abnormal behavior. Bethanechol appears to have a narrow therapeutic window for positive effects; low doses did not reliably alter patient functioning, moderately increased doses appeared to have a palliative effect on patient mood and behavior, and the highest dose was detrimental to patient functioning. Bethanechol does not appear to ameliorate the dementia of AD, but may exert a mildly positive effect on patient behavior and mood.

Cerebellar atrophy demonstrated by computed tomography.

We studied 55 cases of cerebellar atrophy identified by computerized tomography. Atrophy was determined by subjective assessment and objective measurements (superior cerebellar cistern, fourth ventricle, and brainstem). Different patterns of cerebellar atrophy were related to clinical diagnoses. A high incidence of vermal atrophy was observed in primary cerebellar degeneration and chronic alcoholism. More than half the patients with alcoholism had hemispheral atrophy. Vermal atrophy and enlargement of superior cerebellar cisterns (but not hemispheral atrophy) were associated with carcinomatous cerebellar degeneration. Atrophy caused by chronic phenytoin usage showed a specific pattern of enlargement of the cisterna magna, cerebellopontine angle, and superior cerebellar cisterns. Supratentorial atrophy was increased significantly only in the alcoholics. In general, limb ataxia, dysarthria, and nystagmus were related to hemispheral but not to vermal atrophy.

Cerebral atrophy, EEG slowing age, education, and cognitive functioning in suspected dementia.

Seventy-eight hospital patients, 50 years of age or older, were selected for suspected changes in mentation and for the absence of focal or other organic brain disease. They were studied in relation to education, age, cerebral atrophy (by computerized tomography), electroencephalographic (EEG) slowing, and performance in several neuropsychologic tests. Adequate test-retest reliability of the cognitive measures and interjudge reliability of the cerebral atrophy and EEG measures were demonstrated. Stepwise multiple regression analyses suggested the following: (1) EEG slowing is the strongest and most general pathologic influence on cognition in elderly persons without overt brain disease. (2) Cerebral atrophy independently affects primarily the verbal recall of recent and remote information. (3) Age independently affects primarily recent memory for both verbal and nonverbal material. (4) Formal education is a powerful influence that must be accounted for in all studies of the effects of age on cognition.

Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits.

Neuropsychologic and pathologic data are presented for a group of 11 patients with a clinical diagnosis of probable Alzheimer's disease (AD) according to recently proposed criteria. In all cases, the diagnosis was verified by cortical biopsy. In addition, increased cortical plaque counts were associated with greater deficits in language production and comprehension and poorer performance on an index of global mental status. These results suggest that a clinical diagnosis of AD is very accurate when patient selection is restricted to typical cases and that language deficits may provide a useful indicator of severity of disease in AD patients.

Cerebellar atrophy: relationship to aging and cerebral atrophy.

We studied the incidence of computed tomography evidence of cerebellar atrophy in 20 elderly patients with dementia, 20 age-matched controls, and 40 younger normal subjects. Cerebellar vermian atrophy was present in 6 of 20 demented patients, 7 of 20 elderly controls, and 1 of 40 younger controls. There was no other atrophy of infratentorial structures except for occasional enlargement of the cisterna magna and cerebellopontine angle cisterns. Vermian atrophy did not correlate with cerebral atrophy (enlargement of either lateral ventricles or cortical sulci). None of these patients had clinical signs of cerebellar dysfunction. Therefore, atrophy of the cerebellar vermis may occur selectively with aging, without atrophy of the cerebral cortex, and without clinical manifestations.

Natural history of mild cognitive impairment in older persons.

BACKGROUND: Cognitive abilities of older persons range from normal, to mild cognitive impairment, to dementia. Few large longitudinal studies have compared the natural history of mild cognitive impairment with similar persons without cognitive impairment. METHODS: Participants were older Catholic clergy without dementia, 211 with mild cognitive impairment and 587 without cognitive impairment, who underwent annual clinical evaluation for AD and an assessment of different cognitive abilities. Cognitive performance tests were summarized to yield a composite measure of global cognitive function and separate summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. The authors compared the risk of death, risk of incident AD, and rates of change in global cognition and different cognitive domains among persons with mild cognitive impairment to those without cognitive impairment. All models controlled for age, sex, and education. RESULTS: On average, persons with mild cognitive impairment had significantly lower scores at baseline in all cognitive domains. Over an average of 4.5 years of follow-up, 30% of persons with mild cognitive impairment died, a rate 1.7 times higher than those without cognitive impairment (95% CI, 1.2 to 2.5). In addition, 64 (34%) persons with mild cognitive impairment developed AD, a rate 3.1 times higher than those without cognitive impairment (95% CI, 2.1 to 4.5). Finally, persons with mild cognitive impairment declined significantly faster on measures of episodic memory, semantic memory, and perceptual speed, but not on measures of working memory or visuospatial ability, as compared with persons without cognitive impairment. CONCLUSIONS: Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.

The concept of uterine preservation with ovarian malignancies.

A 30-year-old woman with bilateral, recurrent, borderline papillary serous cystadenocarcinoma of the ovary was treated with bilateral oophorocystectomy and omentectomy with uterine preservation. Ten years later, through induction of an artificial endometrial cycle and ovum donation, she conceived twins and delivered two healthy infants. Staging exploratory laparotomy at the time of cesarean delivery was negative for malignancy. This case illustrates the value of uterine preservation for cases in which classical teaching has indicated hysterectomy with bilateral salpingoophorectomy.

Clinical correlates of high signal lesions on magnetic resonance imaging in Alzheimer's disease.

The pathophysiology and clinical significance of high signal lesions, visualized on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD), remain controversial. Since they are known to correlate with vascular disease and vascular risk factors, we reviewed the clinical correlates of periventricular high signal (PVH) and subcortical white matter lesions (WML) in a sample of 106 patients with probable AD, excluding persons with treated vascular risk factors or symptomatic cerebrovascular and cardiovascular disease. Grade 2 PVH were seen in 26 (25%) and scattered WML were identified in 29 (18%). PHV were associated with advancing age and gait disturbance. WML were associated with gait disturbance and incontinence. Neither radiologic finding was related to dementia severity. The findings suggest that these lesions are common in patients with AD even when those with evidence of cerebrovascular disease are excluded; their presence, therefore, should not preclude a diagnosis of AD. Additionally, the data suggest that HSL on MRI may be one of many risk factors associated with functional disability in persons with probable AD.

Differential effects of oral glucose-mediated versus intravenous hyperinsulinemia on circulating androgen levels in women.

OBJECTIVE: To determine whether transient endogenous or continuous exogenous hyperinsulinemia produced different changes in circulating gonadal steroid levels because insulin is a putative regulator of gonadal steroid secretion in polycystic ovarian syndrome (PCOS). DESIGN: An oral glucose tolerance test (OGTT) and a 2-hour euglycemic clamp (+100 microU/mL [718 pmol/L] steady-state insulin levels) were performed in obese patients with PCOS (n = 7) in nonobese patients with PCOS (n = 5), and in age- and weight-matched ovulating normal women (obese normal n = 7, nonobese normal n = 6). RESULTS: Despite increased insulin levels, the levels of T and androstenedione (A) decreased in three of the four groups during the OGTT (nonobese normal women showed a slight increase in T during the OGTT). In contrast, the continuous 2-hour insulin infusion resulted in increased androgen levels. When all four groups were pooled, the difference in the changes in A levels between the two tests was significant, and the difference in T levels between the two tests approached significance. CONCLUSIONS: Transient physiological hyperinsulinemia produced by an oral glucose load was associated with a decrease rather than an increase in circulating androgen levels. The effects on circulating androgen levels of oral glucose-mediated increases in insulin levels were significantly different from those of a continuous intravenous insulin infusion. Sustained hyperinsulinemia produced by exogenous insulin infusion appeared to be required to increase androgen levels in women; transient physiological increases in insulin levels after an oral glucose load were insufficient to produce hyperandrogenism. Postmeal hyperinsulinemia does not contribute to hyperandrogenism in women.

Ruptured pelvic abscess after intrauterine insemination: a case report.

This case reports a serious but previously unreported complication of IUI. Further reports of serious infection would warrant consideration of antibiotic prophylaxis in some cases.

Transcervical placement of a Malecot catheter after hysteroscopic evaluation provides for easier entry into the endometrial cavity for women with histories of difficult intrauterine inseminations and/or embryo transfers: a prospective case series.

OBJECTIVE: To evaluate a new technique designed to improve access to the endometrial cavity through tortuous and/or stenotic endocervical canals in women with histories of difficult IUIs, ETs, or endometrial biopsies. DESIGN: Prospective case series. SETTING: Tertiary care center. PATIENT(S): Women with histories of difficult intrauterine procedures because of tortuous and/or stenotic endocervical canals who continued to undergo treatment. INTERVENTION(S): Hysteroscopic evaluation and/or correction of the endocervix, followed by transcervical placement of a Malecot catheter (CR Bard Inc., Covington, GA) for an average of 10 days. MAIN OUTCOME MEASURE(S): Improvement in the ease of access to the endometrial cavity during IUIs or ETs. RESULT(S): Thirty-two of 36 patients had significantly easier procedures after the placement and removal of a Malecot catheter. CONCLUSION(S): Hysteroscopic evaluation and placement of a Malecot catheter is a useful technique that allows easier entry through the cervical canal in patients in whom previous IUIs, ETs, and endometrial biopsies have been difficult. This procedure may lead to improved pregnancy rates, particularly with IVF-ET, as the ease of ET has been correlated with improved implantation rates.

The effect of baseline complex ovarian cysts on in vitro fertilization outcome.

STUDY OBJECTIVE: To determine the effect of baseline complex ovarian cysts on controlled ovarian hyperstimulation and in vitro fertilization (IVF) outcome. DESIGN: Retrospective analysis with stratification by stimulation regimen and the presence or absence of surgically documented endometriosis. PATIENTS: Two hundred sixty-one women undergoing IVF from May 1, 1989 to December 31, 1990. MAIN OUTCOME MEASURES: The outcome measures assessed were the maximum estradiol (E2) concentration on day of human chorionic gonadotropin (hCG) administration, number of follicles with maximum diameter greater than or equal to 15 mm, number of follicles with maximum diameter greater than or equal to 12 mm, number of days to hCG administration, number of ampules of human menopausal gonadotropin (hMG) used, number of oocytes retrieved and fertilized, number of embryos transferred, and pregnancy and cycle cancellation rates. RESULTS: There were no statistical differences between cyst and noncyst groups in any of the above parameters of IVF performance. In a single subgroup, patients with endometriosis stimulated with hMG and patients with cysts had significantly lower E2 concentrations than patients without cysts. CONCLUSION: The presence of a complex cyst on a baseline ultrasound does not appear to adversely affect IVF cycle outcomes.

A randomized clinical trial to evaluate the clinical effects of split- versus single-dose human menopausal gonadotropins in an assisted reproductive technology program.

OBJECTIVE: To compare the effect of twice (split) versus once (single) daily administration of hMG on assisted reproductive technology (ART) cycle parameters. DESIGN: A randomized clinical trial. SETTING: Hospital-based academic ART program. PATIENTS: A total of 171 patients undergoing their initial ART cycle were enrolled. All patients received one of two hMG regimens and were excluded from the study if they were receiving medications other than leuprolide acetate (LA) and hMG for ovulation induction. INTERVENTIONS: Subjects were randomized to receive an initial dose of 300 IU/d of hMG in either split-dose (i.e., 150 IU twice daily) or single-dose fashion for four successive days after down-regulation with LA. Thereafter, their daily dose was individualized, maintaining a split-or single-dose schedule. All cycles were managed in accordance with our standard ART protocols. MAIN OUTCOME MEASURES: Cancellation rate, total hMG requirements, number of days treated with hMG, E2 and P responses, oocyte yield and maturity, fertilization rate, total number of embryos, embryo quality, number of embryos transferred, implantation rate, clinical and ongoing-delivered pregnancy rates. RESULTS: Split-dose hMG administration resulted in a significantly higher implantation rate, but significantly lower normal and polyspermic fertilization rates than single-dose hMG administration. No significant differences were noted between the two dosage protocols with respect to the other outcome measures. CONCLUSIONS: Split-dose hMG administration may be associated with significantly higher implantation rates; single-dose hMG with significantly higher fertilization rates. Although our data also demonstrate a trend toward higher clinical and ongoing-delivered pregnancy rates with split-dose therapy, demonstration of a significant difference would require a multicenter trial. Based on our data, clinicians may want to consider split-dose therapy for patients with repeated implantation failures.

The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer.

OBJECTIVE: To select patients for day 3 vs. day 5 embryo transfer. DESIGN: Retrospective analysis of assisted reproduction technology (ART) cycles comparing outcomes of day 3 and day 5 transfers. SETTING: ART program of Brigham and Women's Hospital. PATIENT(S): Patients with day 3 or day 5 embryo transfers (n = 221 and 141, respectively). INTERVENTION(S): Cycles with eight or more zygotes were stratified by the number of eight-cell embryos available on day 3 (none, one or two, or three or more). MAIN OUTCOME MEASURE(S): Number of blastocysts, implantation rates, ongoing pregnancy rates, and number of fetal heart beats. RESULT(S): With no eight-cell embryos on day 3, 0% and 33% pregnancies resulted from day 5 vs. day 3 transfers. With one or two eight-cell embryos on day 3, ongoing and high order multiple rates were not different between day 3 and day 5 transfers. With three or more eight-cell embryos, day 5 transfer resulted in a decrease in multiple gestations but no difference in ongoing pregnancy rates compared with day 3 transfer. CONCLUSION(S): With no eight-cell embryos on day 3, a day 3 transfer is warranted. With one or two eight-cell embryos, any benefit of day 5 transfer appears to be equivocal. With three or more eight-cell embryos, day 5 transfer is recommended.

Early diagnosis and treatment of cervical pregnancy in an in vitro fertilization program.

This is a report of three cervical pregnancies, one of which was a heterotopic twin cervical pregnancy that occurred in combination with a single intrauterine pregnancy. Transvaginal ultrasound examination was sufficient to establish the diagnosis in two of three patients, and MRI scanning was conclusive in the third. Early diagnosis lead to intervention before 7 weeks gestation in all cases with no complications. The incidence of cervical pregnancy may be higher in IVF-ET than recognized previously.